Project Summary/Abstract T-cell therapies show incredible promise as treatments for previously intractable relapsed and refractory hematologic cancers. Unfortunately, the incredible efficacy of these therapies has been accompanied by life- threatening side effects caused by overactivation of the immune system, including cytokine release syndrome and neurotoxicity. In some clinical trials, these side effects have resulted in patient deaths. For T-cell therapies to reach their full potential and be applied to a wide range of targets and types of cancer, it will be critical to improve their safety profiles. One method to improve safety is to incorporate molecular switches into T-cell therapies that would allow for precise control over the timing and magnitude of T-cell activity. Chemically induced dimerizers (CIDs) have proven to be powerful tools for controlling cellular signaling pathways and, in turn, biological activity. Unfortunately, classical CID systems have some molecular properties that make them undesirable candidates for switches in human T-cell therapies. Soteria Biotherapeutics seeks to overcome these limitations using antibody-based chemically induced dimerizers (AbCIDs), a new type of molecular switch that was specifically designed for use in human cell therapies. By integrating an AbCID-based molecular switch, the activity of a T-cell therapy will be controllable by a physician through administration of a small molecule drug. This will allow the physician to increase T-cell activity when more efficacy is needed and reduce activity when side effects become apparent. In this SBIR Phase I project, we propose to optimize our chemically regulated AbCID safety switch design and implement it in an improved T-cell therapy for B-cell malignancies. Specific aims will focus on optimization of AbCID expression in a mammalian-cell expression system, evaluation of chemically regulated T-cell activation and cytotoxicity with in vitro primary cell models, and quantification of the in vivo pharmacokinetic properties of the lead AbCID T-cell therapy in mice. Completion of these research aims will directly increase the commercial viability of our lead AbCID-based T-cell therapy product and will lay the groundwork for in vivo efficacy experiments in mouse models in a Phase II project. The successful commercial development of an AbCID-based T-cell therapy will introduce a novel therapeutic option for the treatment of B- cell malignancies and will improve outcomes for patients.